Light-Activated ROS-Responsive Nanoplatform Codelivering Apatinib and Doxorubicin for Enhanced Chemo-Photodynamic Therapy of Multidrug-Resistant Tumors

Abstract

Clinical chemotherapy confronts a challenge resulting from cancer-related multidrug resistance (MDR), which can directly lead to treatment failure. To address it, an innovative approach is proposed to construct a light-activated reactive oxygen species (ROS)-responsive nanoplatform based on a protoporphyrin (PpIX)-conjugated and dual chemotherapeutics-loaded polymer micelle. This system combines chemotherapy and photodynamic therapy (PDT) to defeat the MDR of tumors. Such an intelligent nanocarrier can prolong the circulation time in blood because of the negative polysaccharide component of chondroitin sulfate, and subsequently being selectively internalized by MCF-7/ADR cells [doxorubicin (DOX)-resistant]. When exposed to 635 nm red light, this nanoplatform generates sufficient ROS through the photoconversion of PpIX, further triggering the disassociation of the micelles to release the dual cargoes. Afterward, the released apatinib, serving as a reversal inhibitor of MDR, can recover the chemosensitivity of DOX by competitively inhibiting the P-glycoprotein drug pump in drug-resistant tumor cells, and the excessive ROS has a strong capacity to exert its PDT effect to act on the mitochondria or the nuclei, ultimately causing cell apoptosis. As expected, this intelligent nanosystem successfully reverses tumor MDR via the synergism between apatinib-enhanced DOX sensitivity and ROS-mediated PDT performance.

Keywords: Doxorubicin (DOX); ROS-response; chemo-photodynamic therapy; co-delivery; multidrug resistance; nanoplatform; photodynamic therapy; reactive oxygen species (ROS).